| Autor: |
Specker, E., Bottcher, J., Heine, A., Sotriffer, C. A., Lilie, H., Schoop, A., Muller, G., Griebenow, N., Klebe, G. |
| Zdroj: |
Journal of Medicinal Chemistry; October 2005, Vol. 48 Issue: 21 p6607-6619, 13p |
| Abstrakt: |
Hydroxyethylene sulfones were developed as novel scaffolds against aspartyl proteases. A diastereoselective synthesis has been established to introduce the required side chain decoration with desired stereochemistry. Depending on the substitution of the hydroxyethylene sulfone core, micro- to submicromolar inhibition of HIV-1 protease is achieved for the S-configuration at P1 and R-configuration at the hydroxy-group-bearing backbone atom. This stereochemical preference is consistent with the S,R configuration of amprenavir. The racemic mixture of the most potent derivative (Ki = 80 nM) was separated by chiral HPLC, revealing the S,R,S-enantiomer to be more active (Ki = 45 nM). Docking studies suggested this isomer as the more active one. The subsequently determined crystal structure with HIV-1 protease, cocrystallized from a racemic mixture, exclusively reveals the S,R,S-enantiomer accommodated to the binding pocket. The transition state mimicking hydroxy group of the inhibitor is centered between both catalytic aspartates, while either its carbonyl or sulfonyl group forms H-bonds to the structurally conserved water mediating interactions between ligand and Ile50NH/Ile50NH of both flaps. Biological testing of the stereoisomeric hydroxyethylene sulfones against cathepsin D and β-secretase did not reveal significant inhibition. Most likely, the latter proteases require inverted configuration at the hydroxy group. |
| Databáze: |
Supplemental Index |
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